Identification of myeloid-derived growth factor as a mechanically-induced, growth-promoting angiocrine signal for human hepatocytes

Recently, we have shown that after partial hepatectomy (PHx), an increased hepatic blood flow initiates liver growth in mice by vasodilation and mechanically-triggered release of angiocrine signals. Here, we use mass spectrometry to identify a mechanically-induced angiocrine signal in human hepatic endothelial cells, that is, myeloid-derived growth factor (MYDGF). We show that it induces proliferation and promotes survival of primary human hepatocytes derived from different donors in two-dimensional cell culture, via activation of mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3). MYDGF also enhances proliferation of human hepatocytes in three-dimensional organoids. In vivo, genetic deletion of MYDGF decreases hepatocyte proliferation in the regenerating mouse liver after PHx; conversely, adeno-associated viral delivery of MYDGF increases hepatocyte proliferation and MAPK signaling after PHx. We conclude that MYDGF represents a mechanically-induced angiocrine signal and that it triggers growth of, and provides protection to, primary mouse and human hepatocytes.


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Source data for all quantifications are provided.The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD033942.Gating criteria of flow cytometric analysis and full scans of western blots are provided in Source Data file.
Human blood serum were obtained from one patient with in-situ split liver resection and human blood plasma was obtained from six patients with liver resection (Fig. 1i,j).A brief summary of patient characteristic is provided in the Methods section: "In-situ split liver resection and liver resection".
Not relevant for these patients.For Fig. 1j, we excluded individuals with obesity (BMI > 30 kg/m2).Patients are included consecutively without regard to ethnicity,race or individuals belonging to a certain social group.
Patients are included consecutively without regard to sex and gender.
vivo: Sample size was calculated for control and MYDGF KO mice with Power Calculator 2 and for AAV8-TBG-GFP and AAV8-TBG-MYDGF mice with G*Power Version 3.1.9.3.In vitro: No sample-size calculation was performed (we used different donors of hepatocytes, each containing a different number of cells).Experiments were generally conducted with at least n = 4 biological samples.The precise number (n) of biological samples used to derive statistics is indicated in the figure legends.
For in vivo experiments, mice with improperly perfused (light brown) livers and hemorrhages in the livers were excluded from further analysis.For Western blots, bands with air bubbles were excluded from further analysis.Significant outliers were detected by ESD method (Grubbs' test) in PRISM and excluded from analysis.
For AAV8-TBG-GFP or AAV8-TBG-MYDGF injection, mice were randomized into the respective groups.For 2D in vitro experiments with primary human hepatocytes and EdU proliferation assay with 3D human hepatocyte organoids, a lab member (independent of the experiment) randomly selected which hepatocytes received which treatment.